2-Substituted oxazole-4,5-dicarboxamides

ABSTRACT

Pharmacologically active 2,4,5-trisubstituted oxazoles corresponding to the formula   WHEREIN A represents cyclohexyl, 2-thienyl or a group represented by the formula   WHEREIN R represents a p-phenyl group or one to three substituents selected from the group of hydrogen, hydroxy, lower alkyl, halo, halo-lower alkyl, nitro, cyano, amino, acetamino, carboxy, carbamyl, sulfamoyl and lower alkoxy; R1 and R3 are selected from the group of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, phenyl, phenyl-lower alkyl, hydroxy-lower alkyl, lower acyloxy-lower alkyl, hydroxy, amino, lower alkylideneamino, cycloalkylideneamino, benzylideneamino; R2 and R4 are selected from the group of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, phenyl, phenyl-lower alkyl, hydroxy-lower alkyl, lower acyloxy-lower alkyl; each of the pairs R1, R2 and R3, R4 may also form with the amino nitrogen atom a 5- to 7-membered heterocyclic ring which may contain one other heteroatom selected from N and O.

United States Patent; 191

Tarzia t111 3,869,468 [4 1 Mar. 4, 1975 l l Z-SUBSTITUTED()XAZOLE-4,5-DICARBOXAMIDES Giorgio Tarzia, Roma, Italy- [30] ForeignApplication Priority Data Nov. 15, 1971 Italy 31096/7l [52] US. Cl....260/307 R, 260/247.l, 260/2472 A, 260/268 C, 260/293.67, 424/248,424/250.

[51 1 Int. Cl C07d 85/44 38] Field of Search 260/307 R, 268 C, 293.67,260/247.l, 247.2 A

[56] References Cited OTHER PUBLlCATlONS Morrison et al. OrganicChemistry Allyn & Bacon. Inc. Boston, (l959), pages 534,474,480,484.

Primary li.\uminerRaymond V. Rush Attorney, Agent, or FirmTheodore Post;C. Kenneth Bjork [57] ABSTRACT Pharmacologically active2.4,5-trisubstituted oxazoles corresponding to the formula ONR R A oCONR3R4 wherein A represents cyclohexyl, 2-thienyl or a grouprepresented by the formula wherein R represents a p-phenyl group or oneto three substituents selected from the group of hydrogen, hydroxy,lower alkyl, halo, halo-lower alkyl, nitro, cyano, amino, acetamino,carboxy, carbamyl, sulfamoyl and lower alkoxy; R and R are selected fromthe group of hydrogen, lower alkyl, lower alkenyl, cycloal' kyl, phenyl,phenyl-lower alkyl, hydroxylower alkyl, lower acyloxy-lower alkyl,hydroxy, amino, lower alkylideneamino, cycloalkylideneamino,benzylideneamino; R and R are selected from the group of hydrogen, loweralkyl, lower alkenyl, cycloalkyl. phenyl, phenyl-lower alkyl,hydroxy-lower alkyl, lower acyloxy-lower alkyl; each of the pairs R Rand R R may also form with the amino nitrogen atom a 5- to 7-memberedheterocycllc ring which may contain one other heteroatom selected from Nand O.

13 Claims, No Drawings Z-SUBSTITUTED OXAZOLE-4,S-DICARBOXAMIDES Summaryof the invention This invention relates to new pharmacologically active2,4,5-trisubstituted oxazoles corresponding to the formula If :CONR R Ao oo1t'R R wherein A is cyclohexyl, thienyl or a group representedwherein R represents a p-phenyl group or one to three substituentsselected from the group consisting of hydrogen. hydroxy, lower alkyl,halo, halo-lower alkyl, nitro, cyano, amino, acetamino, carboxy,carbamyl, sulfamoyl and lower alkoxy; R, and R are selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, cycloalkyl,phenyl, phenyl-lower alkyl, hydroxy-lower alkyl, lower acyloxy-loweralkyl, hydroxy, amino, lower alkylideneamino, cycloalkylideneamino,benzylideneamino; R and R are selected from hydrogen, lower alkyl, loweralkenyl, cycloalkyl, phenyl, phenyl-lower alkyl, hydroxy-lower alkyl.acyloxy-lower alkyl; each of the pairs R R and R,,. R, may also formwith the amino nitrogen atom a 5- to 7-membered heterocyclic ring whichmay contain another hetero-atom selected from N and O. In thespecification and claims, lower alkyl and lower alkenyl designate groupswhich are straight or branched and contain from 1 to 6 carbon atoms forthe former and 3 to 6 carbon atoms for the latter; lower alkylidenedesignates 2 to 6 carbon groups; lower acyloxy designates acetoxy,propionyloxy or butyryloxy; cycloalkyl designates 5- to S-memberedrings; phenyl and benzylidene groups in the present invention designatephenyl or halophenyl. lower alkyl phenyl, and lower alkoxy phenyl andbenzylidene, halobenzylidene, lower alkylbenzylidene and loweralkoxybenzylidene. respectively; and halo designates fluoro, chloro orbromo. Representative members of the heterocyclic ring formed by thepair R R or R R in combination with the amino nitrogen are piperidine,pyrrolidine, morpholine and piperazine.

A preferred group of compounds comprises those wherein A is cyclohexyl,thienyl or a group wherein R is hydrogen or p-phenyl or represents fromone to three substituents selected from methyl, chloro. fluoro. methoxy,hydroxy or trifluoromethyl. It is obvious that when only one substituentis present it can be in the ortho, meta or para position of the phenylring. When more than one substituent is present, all their possiblemutual positions are usually available.

Another group of compounds are those wherein R, and R substituentsindependently represent one of hy drogen, lower alkyl, hydroxy,cyclopentyl, cyclohexyl. amino, isopropylideneamino and pmethylbenzylideneamino; R and R in such compounds each independentlyrepresents hydrogen or lower alkyl.

The compounds of this invention have antiintlammatory activity. Somealso have analgesic activity. The biological activity of these compoundsis coupled with a very low toxicity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS A general method of preparationof the inventive compounds comprises the use of a di-lower alkyl esterof4,5-oxazoledicarboxylic acid having an A substituent in the2-position. Alternatively, the corresponding dicarbonyl halides or acidanhydrides may be suitably employed as the starting materials.

When a compound of Formula I is desired wherein the pairs R R and R Rhave the significance given. one of the aforementioned oxazoledicarbonyl halides or acid anhydrides is reacted with at least twoequimolecular proportions of an amine of the formula R HN 5 2 wherein Rand R have the same significance as above. The presence of a solvent isnot essential but advantageous. When a dicarbonyl halide is used as thestarting material, the presence of a tertiary organic base or an excessof the amine reactant of Formula II is required as an acid acceptor forthe hydrogen halide which forms during the reaction. A preferredembodiment of the inventive process involves the use of solvents. Thus.for instance, if oxazole-4,5-dicarboxy esters are used as the startingmaterials, the preferred solvents are selected from the lower alkanolshaving I to 4 carbon atoms or an excess of the amine reactant. Whenoxazole-4,5-dicarbonyl halides are employed, the sol vent is generallyselected from inert organic liquids such as, for example, benzene,toluene, chlorinated hydrocarbons, dioxane and tetrahydrofuran. Thetemperature at which the reaction is carried out is not critical and isgenerally selected in the range between room temperature and the boilingtemperature ofthe solvent.

The compounds of the invention wherein R and/or R represent a loweralkylideneamino or a cycloalkylideneamino or a phenylalkylideneaminogroup are more readily prepared from the corresponding derivativewherein the foregoing groups are amino groups via a condensation with analdehyde or ketone by conventional methods.

The compounds wherein one or more of the groups R,. R R and R is loweracyloxy-lower alkyl are prepared from the corresponding hydroxycompounds through known acylation procedures.

In most cases, the products of the invention are white crystallinesolids which are generally soluble in organic solvents such as, forexample, acetic acid. dioxane, dimethylformamide and dimethylsulfoxide.The compounds which are secondary amides are also fairly soluble inlower alkanols and chloroform. The compounds generally have a very lowsolubility in water. Suitable mice, the compounds of Examples 1, l l,13, 20, 21, 24, 33, 37, 39, 41, 53, and 56 showed anti-inflammatoryactivity. Doses varying from one-twentieth to one-fifth of the LDsovalues per os were found to be highly effective in thecarrageenin-induced edema test. The compounds were administered orallyin dosages varying from to 200 mg/kg and the percent decreases of theinduced edema observed varied from about to about 90. The acute toxicityis generally very low, most of the compounds tested having LD valueshigher than 1000 mg/kg. po. Also, the gastrointestinal ulcerogenicity isvery low when compared with that of other antiinflammatory substancessuch as, for example, phenylbutazone. The preferred route ofadministration of these compounds is by mouth although other routes maybe usefully employed. For this purpose, the substances are embodied inpharmaceutical dosage forms such as tablets, capsules, suspensions andthe like. The

dosage unit may contain the usual excipients such as. for example,starch; gums, alcohols, sugars, fatty acids. cellulose derivatives andtragacanth. The daily dosage rangeis from about 0.5 to about mg/kg ofbody weight, preferably administered in divided doses.

The following non-limitative examples describe in detail the compoundsof this invention and methods for their preparation.

EXAMPLE I:

2-Phenyl-4,5-oxazoledicarboxamide washed with ethanol, dissolved in hotdimethylform-.

amide (DMF) and precipitated by addition of water. Yield 3.5 g., m.p.286-7C.

EXAMPLES 2-36 Pursuant to the method of Example 1, the following4,5-oxazoledicarboxamides are obtained:

Reactants -4,5-oxazoledi- Example carboxylic acid Solvent of No.Compound diethyl ester amine Crystallization M.P.C

2 2-(p-tolyl)-4,5-oxazoledicarboxamide 2-(p-tolyl)- ammonium DMF/water275- hydroxide 3 2-phenyl-4,5-oxazolediearboxylic acid dihydrazide2-phenylhydrazine DMF/water 235 42-(p-ehlorophenyl)-4,5-oxazoledicarammonium DMF/water 285 boxamide2-(p-chlorohydroxide phenyly 5 N,N-dipentyl-2-phenyl-4,5-oxazoledicar'2-phenylpentylamine hexane 159-61 boxamide 6N.N'-dibutyl-2-phenyl-4,5-oxazoledicar- 2-phenylbutylamine hexane 74-5hoxamide 7 N,N-dihenzyl-Z-phenyl-4,5-oxazoledi- Z-phenylbenzylamineethanol 143 earhoxam de 8 N,N-diallyl-2-phenyl-4,5-oxazoledi-2-phenylallylamine ethanol/water 93-4 carboxamide 9N,N'-his(Z-hydroxyethyl)-2-phenyl- 2-phenyl- (2-hydroxy' water 202-4.5oxazoledicarhoxamide ethyl)amine l0N,N'-dimethyl-2-phenyl-4,5-oxazoledi- 2-phenylmethyl carhoxamide amineDMF/ethyl ether I I l N,N-dicyclohexyl-2-phenyl-4,5-oxa-2-phenylcyclohexylethanol l l4-5 zoledicarboxamide amine l2N,N'-dipropyl-2-pheny|-4,5-oxazo|e- 2-phenylpropylamine ethanol-water X6dicarhoxamide 13 NN -diethyl2phenyl-4,5-oxazole- Z-phenylethylamineethanol 129-30 dicarhoxamide l4 4,5 his( morpholinocarbonyl )22-phenylmorpholine ethanol 186 -phenyloxazolc l5 N,N "his(B-hydroxypropyl )-2-phenyl- Z-phenyl- 3 hydroxywater I88-4,5oxazoledicarhoxamide propylamine l6 N,N-diisopropyl-2-( p-tolyl)-4,5- 2-( p-tolyl isopropylmethanol l29-30 -oxazolediearhoxamide aminel7 N,N '-dicyclohexyl-2-( p-tolyl )-4,5- 2-( p-tolyl eyclohexylethanoll55-7 -oxazoledicarhoxamide amine l X N,N -diethyl-2-( p-tolyl)-4,5-oxa- 2-(p-tolyl ethylamine ethanol l 79-80 zoledicarhoxamide l94,5-bis(piperidinocarbonyl)-2- 2-phenylpiperidine ligroin lOlphenyloxazole 2O N,N'-diisobutyl-2-phenyl-4,S-oxa2-phenylisobutylaethanol-water 9l-2 zoledicarboxamide mine 2t N,N-diisopropyl-2-phenyl-4,S-oxazole- 2-phenylisopropylligroin I28dicarhoxamide amine 22 2(3,4,5-trimethoxyphenyl)-4,5-oxa-2-(3.4.5-triammonium hydro- DMF diethyl- 299-30l zoledicarboxamidemethoxyphenyl)- xide ether 23 2-(p-methoxyphenyl)-4,5-oxazole-2-(p-methoxyammonium hy- DMF/diethyl- 280 dicarhoxamide phenyl) droxideether 24 2-(p-l'luorophenyl)-4,5oxazole- 2-(p-t'luoroammonium hy-DMF/diethyl- 302-4 dicarhoxamide phenyl)- droxide ether 252-(3,5-dimethoxyphenyl)-4,5-oxazole- 2-(3,5-dimeammonium DMF/ethyl269-7] dicarhoxamide thoxyphenyU- hydroxide ether 26Z-tm-tolyl)-4,S-oxazoledicarhoxamide 2-(m-tolyllammonium DMF/ethyl320-23 hydroxide ether 27 2-( o-tolyl )-4,5-oxazoletliearhoxamideZ-(o-tolyl l ammonium DMF/water 95 hydroxide 28N,N-dicycloheptyl2-phenyl-4,5- 2-phenylcycloheptylmethanol I24'oxazoletlicurhoxamide amine 29 2-(p-tcrt-hutyl)-phenyl-4,5-oxazole-Z-tp-tert. ammonium ethanol- 3l4-5 dicarhoxamide butyl)phenylhydroxidewater Continued Reactants -4,5-oxazoledi' Example 7 carboxylic acidSolvent of No. Compound diethyl ester amine Crystallization M.P.C

3t) 2-( m-trilluoromethylphenyl )-4,5-oxazo|e Z-(m-trifluoammoniumcthanol- 327-28 dicarhoxamidc romethylhydroxide water phenyl)- 3|Z-(m-mcthoxyphenyl )-4,5 oxazoledicar 2-(m-methoxyammonium DM F/cthyl279 -R I boxamidc phenyl)- hydroxide ether 32 24 m-chlorophenyl)-4,5oxazoledicar- 2-( m-chloroammonium DMF/ethyl i L boxamide phenyl)-hydroxide ether 33 Z-(o-fluorophenyl)4,5-oxazolediear-2-(o-fluoroammonium DMF/ethyl Zotlfltl boxamide phenyl)- hydroxide etherI 34 N,N'-dicyclohexyl-2-(p-fluorophenyl)- 2-(p-fluorocyclohexylethanol'l38-4ll -4,S-oxazoledicarboxamide phenyl)- amine 352-(o-chlorophenyl)-4,5-oxazoledicar- Z-(o-chloroammonium DMF/ethyl 282-9boxamide phenyllhydroxide ether 36 2-( m-fluorophenyl)-4,5-oxazoledicar- 2-( m-fluoroammonium DMF/ethyl 310-3 boxamidephenyl)- hydroxide ether EXAMPLE 37: tron is added to 10 g. of2-phenyl-4,5-

2-( 2Thienyl )-4,5-oxazoledicarboxamide The title compound is preparedby following the procedure of Example 1, using 2 thienyl-4,5-oxazoledicarboxylic acid diethyl ester as a starting material. M.p.285287C.. crystallized from ethanol.

EXAM PLE 3 8: 2-Cyclohexyl-4.5-oxazoledicarboxamide oxazoledicarboxylicacid diethyl ester in 50 ml. of methanol. The mixture is stirred for twohours and poured into ice water and the mixture adjusted to pH 3 withaqueous 10% HCl. The resulting crude precipitate is dissolved in aqueous10% sodium hydroxide and recovered as the pure titular compound byacidifi cation of the solution with aqueous 10% HCl. M.p. 2l82l9C..yield 5.4 g.

EXAMPLES 42-46 Pursuant to the procedure described in Example 41, thefollowing 4,5-oxazoledicarbohydroxamic acids are prepared.

Reactants -4,5-oxazoledi- Example COMPOUND carboxylic acid No.-4,5-oxazoledicarbohydroxamic acid diethyl ester amine M.P.Cl

42 2-(p-tolyl)- Z-(p-tolyl hydroxylamine 200 43 2'tm-methoxyphenyl 2(omethoxyphenyl hydroxylamine 188-90 44 2-(p-chlorophenyl)-Z-(p-chlorophcnyllhydroxylamine 204-5 45 2(p-methoxyphenyl) 2-(pmethoxyphenyl) hydroxylamine 215-6 46 Z-(p-fluorophenyh-2'(p-fluorophenyl)- hydroxylamine l97-8 EXAM PLE 39: Z-Phenyl-NN '-bis-(3-acetoxypropyl)-4,5- oxazoledicarboxamide EXAMPLE 40: Z-Phenyl-NN-bis-( 2-acetoxyethyl )-4,5-

oxazoledicarboxamide The compound is prepared by the procedure of theforegoing example, by using as a starting material the compound ofExample 9. M.p. 130135C.. crystallized from ethanol.

EXAMPLE 4]: 2-Phenyl-4,5-oxazoledicarbohydroxamic acid To a solution of4.7 g. of hydroxylamine hydrochloride in 60 ml. of methanol 8.5 g. ofsodium hydroxide dissolved in 60 ml. of methanol is added. Afterfiltering off the precipitated sodium chloride, the resulting solu- LitLII

EXAM PLE 47: Z-Phenyl-N ,N .N N '-tetrapropyl-4,5

- oxazoledicarboxamide Three g. of 2-phenyl-4,5-oxazoledicarboxylic aciddiethyl ester is added to a solution containing 2.4 g. of potassiumhydroxide in 40 ml. of ethanol. After stirring for 2 hours at roomtemperature the ethanol is distilled off in vacuo at about 35C. and theresidual aqueous solution is adjusted to pH 2 with aqueous 1071 HCl. Themixture is stirred for 40 minutes at room temperature with ml. of ethylacetate and the organic layer is separated and washed with aqueoussaturated sodium chloride. On evaporation of the dried organic solution,2-phenyl-4,5-oxazoledicarboxylic acid is ob tained in a practicallyquantitative yield. This product may be used as such for the furtherreaction steps. A pure sample of the compound obtained bycrystallization from ethyl acetate melts at 216C. The crude acid istreated with 30 ml. of SOCL and 1 ml. of dimethylformamide for 1 hour,and after elimination of the evolved hydrogen chloride in evaporationunder vacuum is dissolved in 30 ml. of benzene and 12 ml.ofdipropylamine in 50 ml. of benzene is added thereto with cooling.After one hour, the mixture is diluted with benzene and washed severaltimes with aqueous 5% HCl. The organic solution is dried and evaporatedin vacuo to give the title compound which, after crystalli zation fromhexane, melts at 85C. Yield 3.2 g.

EXAMPLES 48-55 phenyl)-4.S-oxazoledicarboxylic acid diethyl ester.2-(p-hydroxyphenyl)-4.5-oxazoledicarboxamidc is obtained.

Alternatively the title compound may be prepared The following compoundsare prepared by the proce- 5 through alkaline hydrolysis with l N. NaOHof crude dure of Example 47 by using the appropriate amine and 2(p-methanesulfonyloxyphenyD-4.5- oxazole starting reactants.oxazoledicarboxamide which is turn is obtained from Rcactants-4,5-oxazoledi- M.P.C. Example carboxylic acid Solvent of of B.P.

No. Compound diethyl ester amine CRYSTALLIZA Clmm Hg.

TION

48 N,N'-2-triphenyl-4,5-oxazoledicarboxamide 2-phenylaniline acetone203-4 49 4,5-bis-(pyrrolidinocarbonyl)-2-phenyl- 2-phenylpyrrolidineethyl 178 oxazole acetate 50 N,N ,N',N '-tetracyclohexyl-2-phenyl4,5-2-phenyldicyclohexethanol 213-4 oxazoledicarboxamide ylamine 5lN,N,N,N'-tetrabenzyl-2-phenyl-4,S-oxa- 2-phenyldibenzylethanol 143-4zoledicarboxamide amine 52 N,N-dicyclooctyl-2-phenyl-4,5-0xa-Z-phenylcyclooctylmethanol 94-5 zoledicarboxamide amine 53N,N-dicyclopentyl-2-phenyl-4,5-oxa- 2-phenylcyclopenbenzene- 159-63zoledicarboxamide tylamine -ligroin 54N,N,N'.N'-tetramethyl-2-phenyl-4.5- 2-phenyldimethylaeetonel-loxazolediearboxamide amine -hexane 55 N,N.N,N'-tetraethyl-2-phenyl-4,5-2-phenyldiethylacetonel90/0.6

-oxazoledicarboxamide amine hexane EXAMPLE 56: the corresponding diethylester according to the procedure of Exam le 1. The title com ound meltsabove 2-Phenyl-4,5-oxazoledicarboxylie acid 300C p pbls'sopropyl'denehydrazlde The procedure similar to that of Example l isused to Three hundred mg. of 2-phenyl4,5- prepare the followingcompounds from the analogous oxazoledicarboxylie acid dihydrazide isheated in 15 dicarboxylic acid diethyl esters: ml. of acetone for 30minutes. On dilution with 50 ml.Z-(m-nitrophenyl)-4,5-oxazoledicarboxamide of hexane. the title compoundis recovered in a practi- Z-(p-nitrophenyl)-4.5-oxazoledicarboxamidecally quantitative yield. M.p. 230C.2-(p-cyanophenyl)-4.5-oxazoledicarboxamide EXAMPLE (p carboxyphenyl) 4.5oxazoled|carboxamide 7 2-(p-carbamylphenyl)-4,5-oxazoledicarboxamide h Fl 2-(o-aminophenyl)-4,5-oxazoledicarboxamide-bis-methylbenzyhdenehydrazide EXAMPLE 61 A mixture of ll g. of2-phenyl-4,5- oxazoledicarboxylic acid dihydrazide and ll g. ofptolualdehyde in 200ml. of benzene is refluxed for 6 hours while thewater which forms during the reaction is distilled off azeotropically.The title compound which precipitates on concentration of the solvent iscrystallized from a mixture of dichloromethane and hexane. Yield 15 g.,m.p. 2735C.

EXAMPLE 58:

Z-Phenyl-4,5-oxazoledicarboxylic acid bis-cyelohexylidenehydrazide Thetitle compound is prepared by the procedure of Example 57, substitutingcyclohexanone in place of p tolaldehyde. Mtp. l43-5C. (crystallized froma mixture of dichloromethane and hexane).

EXA M PLE 60: 2-( p-Hydroxyphenyl )-4,5-oxazoledicarboxamide Pursuant tothe procedure of Example 1 and employing as the starting material thecrude Z-(p-hydroxy- The 4,5-oxazoledicarboxylic acid diethyl esterswhich are used as intermediates for the preparation of the inventivecompounds are prepared according to the procedure described by NobuoSomo et al. in Chem. Pharm. Bull. 15 (5) 619. 1967 for 2-phenyl-4.5-oxazoledicarboxylic acid diethyl ester. The imidate salts required forthe preparation of these oxazole derivatives are prepared according toknown literature methods. In the case of ortho-substituted benzimidatesalts, the procedure of L. Weintraub et al., J. Org. Chem. 33. No. 4,1679, has been used. The following new esters have been prepared:

5 o COOC H R R M.P.C. (or

B.P./nim Hg.)

3CH 40-2 (light petroleum) 4-OCH;, 72-4 (cyclohexanc) 4CH;,(cyclohexane) 4Cl 64-5 (cyclohexane) 4F 82-5(cyclohexane) 3Cl 73-5(cyclohexane) 3,4.5-OCH;, 108-10 (ethanol) 2-(2-Thienyl)-4.5-oxazoledicarboxylic acid dicthyl esterl-Cyclohcxy'l-lfioxazoledicarboxylic acid diethyl ester 90-92C.(cyclohexane) We claim: 1. A compound represented by the formula CONR R2 A O CONR R wherein A represents cyclohexyl. Z-thienyl or a groupcorresponding to the formula .bon

kyl, hydroxy, amino, lower alkylideneamino, 5 to 8 caratomcycloalkylideneamino and ben- 2 ylideneamino; R and R are selected fromthe group of hydrogen, lower alkyl, lower alkenyl. 5 to 8 carbon atomcycloalkyl, phenyl, phenyl-lower alkyl, hydroxylower alkyl, 2 to 4carbon atom straight-chain alkanoyloxy'lower alkyl; each of the pairsR,R and R;,R, are the same; and each of the pairs R R and R R may alsoform with the amino nitrogen atom pyrrolidinyl, piperazinyl, piperidinylor morpholinyl.

2. The compound of claim 1 which is Z-phenyl- 4,5-oxazoledicarboxamide.

3. The compound of claim l which isNNalicyclohexyl-2-phenyl-4,5-oxazoledicarboxamide.

4. The compound of claim l which is N,N-diethyl-2-phenyl-4,5-oxazoledicarboxamide.

5. The compound of claim 1 which is N,N-

diisobutyl-2-phenyl-4,5 -oxazoledicarboxamide.

6. The compound of claim 1 which is NNdiisopropyl-2phenyl-4,5-oxazoledicarboxamide.

7. The compound of claim I which is2'(pfluorophenyl)-4,5-oxazoledicarboxamide.

8. The compound of claim 1 which is2-(ofluorophenyl)-4,5-oxazoledicarboxamide.

9. The compound of claim 1 which is Z-(Z-thienyh-4,5-oxazoledicarboxamide.

10. The compound of claim 1 which is Z(phenyl)-N,N'-bis-(3-acetoxypropyl)-4,5- oxazoledicarboxamide.

11. The compound of claim 1 which is Z-phenyl-4,5-oxazoledicarbohydroxamic acid.

12. The compound of claim 1 which isN,N'-dicyclopentyl-2-phenyl-4,5-oxazoled:icarboxamide.

13. The compound of claim 1 which is 2-phenyl- 4,5-oxazoledicarboxylicacid bisisopropylidenehydrazide.

1. A COMPOUND REPRESENTED BY THE FORMULA
 2. The compound of claim 1which is 2-phenyl-4,5-oxazoledicarboxamide.
 3. The compound of claim 1which is N,N''-di-cyclohexyl-2-phenyl-4,5-oxazoledicarboxamide.
 4. Thecompound of claim 1 which isN,N''-diethyl-2-phenyl-4,5-oxazoledicarboxamide.
 5. The compound ofclaim 1 which is N,N''-diisobutyl-2-phenyl-4, 5-oxazoledicarboxamide. 6.The compound of claim 1 which is N,N''-diisopropyl-2phenyl-4,5-oxazoledicarboxamide.
 7. The compound of claim 1 which is2-(p-fluorophenyl)-4,5-oxazoledicarboxamide.
 8. The compound of claim 1which is 2-(o-fluorophenyl)-4,5-oxazoledicarboxamide.
 9. The compound ofclaim 1 which is 2-(2-thienyl)-4,5-oxazoledicarboxamide.
 10. Thecompound of claim 1 which is 2-(phenyl)-N,N''-bis-(3-acetoxypropyl)-4,5-oxazoledicarboxamide.
 11. The compound ofclaim 1 which is 2-phenyl-4,5-oxazoledicarbohydroxamic acid.
 12. Thecompound of claim 1 which isN,N''-di-cyclopentyl-2-phenyl-4,5-oxazoledicarboxamide.
 13. The compoundof claim 1 which is 2-phenyl-4,5-oxazoledicarboxylic acidbis-isopropylidenehydrazide.